Infection, delirium, and risk of dementia in patients with and without white matter disease on previous brain imaging: a population-based study.

BACKGROUND: The increased risk of dementia after delirium and infection might be influenced by cerebral white matter disease (WMD). In patients with transient ischaemic attack (TIA) and minor stroke, we assessed associations between hospital admissions with delirium and 5-year dementia risk and between admissions with infection and dementia risk, stratified by WMD severity (moderate or severe vs absent or mild) on baseline brain imaging. METHODS: We included patients with TIA and minor stroke (National Institutes of Health Stroke Score <3) from the Oxford Vascular Study (OXVASC), a longitudinal population-based study of the incidence and outcomes of acute vascular events in a population of 94 567 individuals, with no age restrictions, attending eight general practices in Oxfordshire, UK. Hospitalisation data were obtained through linkage to the Oxford Cognitive Comorbidity, Frailty, and Ageing Research Database-Electronic Patient Records (ORCHARD-EPR). Brain imaging was done using CT and MRI, and WMD was prospectively graded according to the age-related white matter changes (ARWMC) scale and categorised into absent, mild, moderate, or severe WMD. Delirium and infection were defined by ICD-10 coding supplemented by hand-searching of hospital records. Dementia was diagnosed using clinical or cognitive assessment, medical records, and death certificates. Associations between hospitalisation with delirium and hospitalisation with infection, and post-event dementia were assessed using time-varying Cox analysis with multivariable adjustment, and all models were stratified by WMD severity. FINDINGS: From April 1, 2002, to March 31, 2012, 1369 individuals were prospectively recruited into the study. Of 1369 patients (655 with TIA and 714 with minor stroke, mean age 72 [SD 13] years, 674 female and 695 male, and 364 with moderate or severe WMD), 209 (15%) developed dementia. Hospitalisation during follow-up occurred in 891 (65%) patients of whom 103 (12%) had at least one delirium episode and 236 (26%) had at least one infection episode. Hospitalisation without delirium or infection did not predict subsequent dementia (HR 1·01, 95% CI 0·86-1·20). In contrast, hospitalisation with delirium predicted subsequent dementia independently of infection in patients with and without WMD (2·64, 1·47-4·74; p=0·0013 vs 3·41, 1·91-6·09; p<0·0001) especially in those with unimpaired baseline cognition (cognitive test score above cutoff; 4·01, 2·23-7·19 vs 3·94, 1·95-7·93; both p≤0·0001). However, hospitalisation with infection only predicted dementia in those with moderate or severe WMD (1·75, 1·04-2·94 vs 0·68, 0·39-1·20; pdiff=0·023). INTERPRETATION: The increased risk of dementia after delirium is unrelated to the presence of WMD, whereas infection increases risk only in patients with WMD, suggesting differences in underlying mechanisms and in potential preventive strategies. FUNDING: National Institute for Health and Care Research and Wellcome Trust.

Association of Incidentally Discovered Covert Cerebrovascular Disease Identified Using Natural Language Processing and Future Dementia.

Background Covert cerebrovascular disease (CCD) has been shown to be associated with dementia in population-based studies with magnetic resonance imaging (MRI) screening, but dementia risk associated with incidentally discovered CCD is not known. Methods and Results Individuals aged ≥50 years enrolled in the Kaiser Permanente Southern California health system receiving head computed tomography (CT) or MRI for nonstroke indications from 2009 to 2019, without prior ischemic stroke/transient ischemic attack, dementia/Alzheimer disease, or visit reason/scan indication suggestive of cognitive decline or stroke were included. Natural language processing identified incidentally discovered covert brain infarction (id-CBI) and white matter disease (id-WMD) on the neuroimage report; white matter disease was characterized as mild, moderate, severe, or undetermined. We estimated risk of dementia associated with id-CBI and id-WMD. Among 241 050 qualified individuals, natural language processing identified 69 931 (29.0%) with id-WMD and 11 328 (4.7%) with id-CBI. Dementia incidence rates (per 1000 person-years) were 23.5 (95% CI, 22.9-24.0) for patients with id-WMD, 29.4 (95% CI, 27.9-31.0) with id-CBI, and 6.0 (95% CI, 5.8-6.2) without id-CCD. The association of id-WMD with future dementia was stronger in younger (aged <70 years) versus older (aged ≥70 years) patients and for CT- versus MRI-discovered lesions. For patients with versus without id-WMD on CT, the adjusted HR was 2.87 (95% CI, 2.58-3.19) for older and 1.87 (95% CI, 1.79-1.95) for younger patients. For patients with versus without id-WMD on MRI, the adjusted HR for dementia risk was 2.28 (95% CI, 1.99-2.62) for older and 1.48 (95% CI, 1.32-1.66) for younger patients. The adjusted HR for id-CBI was 2.02 (95% CI, 1.70-2.41) for older and 1.22 (95% CI, 1.15-1.30) for younger patients for either modality. Dementia risk was strongly correlated with id-WMD severity; adjusted HRs compared with patients who were negative for id-WMD by MRI ranged from 1.41 (95% CI, 1.25-1.60) for those with mild disease on MRI to 4.11 (95% CI, 3.58-4.72) for those with severe disease on CT. Conclusions Incidentally discovered CCD is common and associated with a high risk of dementia, representing an opportunity for prevention. The association is strengthened when discovered at younger age, by increasing id-WMD severity, and when id-WMD is detected by CT scan rather than MRI.

Stratifying Future Stroke Risk with Incidentally Discovered White Matter Disease Severity and Covert Brain Infarct Site.

BACKGROUND: Covert cerebrovascular disease (CCD) includes white matter disease (WMD) and covert brain infarction (CBI). Incidentally discovered CCD is associated with increased risk of subsequent symptomatic stroke. However, it is unknown whether the severity of WMD or the location of CBI predicts risk. OBJECTIVES: The aim of this study was to examine the association of incidentally discovered WMD severity and CBI location with risk of subsequent symptomatic stroke. METHOD: This retrospective cohort study includes patients aged ≥50 years old in the Kaiser Permanente Southern California health system who received neuroimaging for a nonstroke indication between 2009 and 2019. Incidental CBI and WMD were identified via natural language processing of the neuroimage report, and WMD severity was classified into grades. RESULTS: A total of 261,960 patients received neuroimaging; 78,555 patients (30.0%) were identified to have incidental WMD and 12,857 patients (4.9%) to have incidental CBI. Increasing WMD severity is associated with an increased incidence rate of future stroke. However, the stroke incidence rate in CT-identified WMD is higher at each level of severity compared to rates in MRI-identified WMD. Patients with mild WMD via CT have a stroke incidence rate of 24.9 per 1,000 person-years, similar to that of patients with severe WMD via MRI. Among incidentally discovered CBI patients with a determined CBI location, 97.9% are subcortical rather than cortical infarcts. CBI confers a similar risk of future stroke, whether cortical or subcortical or whether MRI- or CT-detected. CONCLUSIONS: Increasing severity of incidental WMD is associated with an increased risk of future symptomatic stroke, dependent on the imaging modality. Subcortical and cortical CBI conferred similar risks.

Development of Parkinson Disease and Its Relationship with Incidentally Discovered White Matter Disease and Covert Brain Infarction in a Real-World Cohort.

OBJECTIVE: This study aimed to examine the relationship between covert cerebrovascular disease, comprised of covert brain infarction and white matter disease, discovered incidentally in routine care, and subsequent Parkinson disease. METHODS: Patients were ≥50 years and received neuroimaging for non-stroke indications in the Kaiser Permanente Southern California system from 2009 to 2019. Natural language processing identified incidentally discovered covert brain infarction and white matter disease and classified white matter disease severity. The Parkinson disease outcome was defined as 2 ICD diagnosis codes. RESULTS: 230,062 patients were included (median follow-up 3.72 years). A total of 1,941 Parkinson disease cases were identified (median time-to-event 2.35 years). Natural language processing identified covert cerebrovascular disease in 70,592 (30.7%) patients, 10,622 (4.6%) with covert brain infarction and 65,814 (28.6%) with white matter disease. After adjustment for known risk factors, white matter disease was associated with Parkinson disease (hazard ratio 1.67 [95%CI, 1.44, 1.93] for patients <70 years and 1.33 [1.18, 1.50] for those ≥70 years). Greater severity of white matter disease was associated with increased incidence of Parkinson disease(/1,000 person-years), from 1.52 (1.43, 1.61) in patients without white matter disease to 4.90 (3.86, 6.13) in those with severe disease. Findings were robust when more specific definitions of Parkinson disease were used. Covert brain infarction was not associated with Parkinson disease (adjusted hazard ratio = 1.05 [0.88, 1.24]). INTERPRETATION: Incidentally discovered white matter disease was associated with subsequent Parkinson disease, an association strengthened with younger age and increased white matter disease severity. Incidentally discovered covert brain infarction did not appear to be associated with subsequent Parkinson disease. ANN NEUROL 2022;92:620-630.

Risk Factors for Silent Brain Infarcts and White Matter Disease in a Real-World Cohort Identified by Natural Language Processing.

OBJECTIVE: To assess the frequency of silent brain infarcts (SBIs) and white matter disease (WMD) and associations with stroke risk factors (RFs) in a real-world population. PATIENTS AND METHODS: This was an observational study of patients 50 years or older in the Kaiser Permanente Southern California health system from January 1, 2009, through June 30, 2019, with head computed tomography or magnetic resonance imaging for nonstroke indications and no history of stroke, transient ischemic attack, or dementia. A natural language processing (NLP) algorithm was applied to the electronic health record to identify individuals with reported SBIs or WMD. Multivariable Poisson regression estimated risk ratios of demographic characteristics, RFs, and scan modality on the presence of SBIs or WMD. RESULTS: Among 262,875 individuals, the NLP identified 13,154 (5.0%) with SBIs and 78,330 (29.8%) with WMD. Stroke RFs were highly prevalent. Advanced age was strongly associated with increased risk of SBIs (adjusted relative risks [aRRs], 1.90, 3.23, and 4.72 for those aged in their 60s, 70s, and ≥80s compared with those in their 50s) and increased risk of WMD (aRRs, 1.79, 3.02, and 4.53 for those aged in their 60s, 70s, and ≥80s compared with those in their 50s). Magnetic resonance imaging was associated with a reduced risk of SBIs (aRR, 0.87; 95% CI, 0.83 to 0.91) and an increased risk of WMD (aRR, 2.86; 95% CI, 2.83 to 2.90). Stroke RFs had modest associations with increased risk of SBIs or WMD. CONCLUSION: An NLP algorithm can identify a large cohort of patients with incidentally discovered SBIs and WMD. Advanced age is strongly associated with incidentally discovered SBIs and WMD.

Experience of Parents of Children with Genetically Determined Leukoencephalopathies Regarding the Adapted Health Care Services During the COVID-19 Pandemic.

Parents of children with genetically determined leukoencephalopathies play a major role in their children's health care. Because of the COVID-19 pandemic, many health care services were suspended, delayed or delivered remotely with telemedicine. We sought to explore the experience of parents of children with genetically determined leukoencephalopathies during the pandemic given the adapted health care services. We conducted semistructured interviews with 13 parents of 13 affected children. Three main themes were identified using thematic analysis: perceived impact of COVID-19 on health care services, benefits and challenges of telemedicine, and expectations of health care after the pandemic. Parents perceived a loss/delay in health care services while having a positive response to telemedicine. Parents wished telemedicine would remain in their care after the pandemic. This is the first study assessing the impact of COVID-19 on health care services in this population. Our results suggest that parents experience a higher level of stress owing to the shortage of services and the children's vulnerability.

Association of Silent Cerebrovascular Disease Identified Using Natural Language Processing and Future Ischemic Stroke.

BACKGROUND AND OBJECTIVES: Silent cerebrovascular disease (SCD), comprising silent brain infarction (SBI) and white matter disease (WMD), is commonly found incidentally on neuroimaging scans obtained in routine clinical care. Their prognostic significance is not known. We aimed to estimate the incidence of and risk increase in future stroke in patients with incidentally discovered SCD. METHODS: Patients in the Kaiser Permanente Southern California (KPSC) health system aged ≥50 years, without prior ischemic stroke, transient ischemic attack (TIA), or dementia/Alzheimer disease receiving a head CT or MRI between 2009 and 2019 were included. SBI and WMD were identified by natural language processing (NLP) from the neuroimage report. RESULTS: Among 262,875 individuals receiving neuroimaging, NLP identified 13,154 (5.0%) with SBI and 78,330 (29.8%) with WMD. The incidence of future stroke was 32.5 (95% confidence interval [CI] 31.1, 33.9) per 1,000 patient-years for patients with SBI: 19.3 (95% CI 18.9, 19.8) for patients with WMD and 6.8 (95% CI 6.7, 7.0) for patients without SCD. The crude hazard ratio (HR) associated with SBI was 3.40 (95% CI 3.25 to 3.56) and for WMD 2.63 (95% CI 2.54 to 2.71). With MRI-discovered SBI, the adjusted HR was 2.95 (95% CI 2.53 to 3.44) for those <65 years of age and 2.15 (95% CI 1.91 to 2.41) for those ≥65. With CT scan, the adjusted HR was 2.48 (95% CI 2.19 to 2.81) for those <65 and 1.81 (95% CI 1.71 to 1.91) for those ≥65. The adjusted HR associated with a finding of WMD was 1.76 (95% CI 1.69 to 1.82) and was not modified by age or imaging modality. DISCUSSION: Incidentally discovered SBI and WMD are common and associated with increased risk of subsequent symptomatic stroke, representing an important opportunity for stroke prevention.

Association of Left Ventricular Hypertrophy and Atrial Fibrillation with Hemorrhagic Evolution of Small Vessel Disease.

OBJECTIVES: Cerebral small vessel disease (SVD) is often associated with hypertension and may evolve towards intracerebral hemorrhage (ICH) or lacunar ischemic stroke. However, the factors favoring the evolution towards ICH or lacunar stroke are not well understood. MATERIALS AND METHODS: This retrospective study included 326 consecutive patients (71.1±13.2 years, 38% women): 143 with deep ICH and 183 with lacunar lesions (LL) <2 cm, which were visible in a deep location on brain CT scan. Among LL patients, 143 had a small-artery occlusion (SAO) stroke according to the TOAST classification. Clinical characteristics plus laboratory and neuroradiological variables of these patients had been prospectively collected and a subgroup underwent echocardiography. RESULTS: In multivariate analysis, ICH patients (97% hypertensive), compared to SAO patients (89% hypertensive), had greater left ventricular wall thickness (LVWT; OR 4.15, 95%CI 1.64-10.53, for those with LVWT ≥ 1.4 cm, 70% of whom were hemorrhagic) and lower prevalence of white matter lesions (OR 0.30, 95%CI 0.13-0.70), ever smokers (OR 0.39, 95%CI 0.18-0.82) and diabetics (OR 0.29, 95% CI 0.10-0.84). Moreover, ICH patients had a greater prevalence of atrial fibrillation than LL patients (OR 3.14, 95%CI 1.11-8.93), and so they were more often anticoagulated. CONCLUSIONS: Most SVD patients were hypertensive, but those evolving towards ICH were characterized by organ damage at the cardiac level (increase in LVWT and atrial fibrillation), while those evolving towards lacunar stroke were characterized by a higher prevalence of smokers and diabetics, and by organ damage at the cerebral level (white matter lesions).

Volume of White Matter Hyperintensities, and Cerebral Micro-Bleeds.

PURPOSE: In the past years the significance of white matter hyperintensities (WMH) has gained raising attention because it is considered a marker of severity of different pathologies. Another condition that in the last years has been assessed in the neuroradiology field is cerebral microbleeds (CMB). The purpose of this work was to evaluate the association between the volume of WMH and the presence and characteristics of CMB. MATERIAL AND METHODS: Sixty-five consecutive (males 45; median age 70) subjects were retrospectively analyzed with a 1.5 Tesla scanner. WMH volume was quantified with a semi-automated procedure considering the FLAIR MR sequences whereas the CMB were studied with the SWI technique and CMBs were classified as absent (grade 1), mild (grade 2; total number of CMBs: 1-2), moderate (grade 3; total number of CMBs: 3-10), and severe (grade 4; total number of CMBs: >10). Moreover, overall number of CMBs and the maximum diameter were registered. RESULTS: Prevalence of CMBs was 30.76% whereas WMH 81.5%. Mann-Whitney test showed a statistically significant difference in WMH volume between subjects with and without CMBs (p < 0.001). Pearson analysis showed significant correlation between CMB grade, number and maximum diameter and WMH. The better ROC area under the curve (Az) was obtained by the hemisphere volume with a 0.828 (95% CI from 0.752 to 0,888; SD = 0.0427; p value = 0.001). The only parameters that showed a statistically significant association in the logistic regression analysis were Hemisphere volume of WMH (p = 0.001) and Cholesterol LDL (p = 0.0292). CONCLUSION: In conclusion, the results of this study suggest the presence of a significant correlation between CMBs and volume of WMH. No differences were found between the different vascular territories.

Cumulative incidence and risk factors for radiation induced leukoencephalopathy in high grade glioma long term survivors.

The incidence and risk factors associated with radiation-induced leukoencephalopathy (RIL) in long-term survivors of high-grade glioma (HGG) are still poorly investigated. We performed a retrospective research in our institutional database for patients with supratentorial HGG treated with focal radiotherapy, having a progression-free overall survival > 30 months and available germline DNA. We reviewed MRI scans for signs of leukoencephalopathy on T2/FLAIR sequences, and medical records for information on cerebrovascular risk factors and neurological symptoms. We investigated a panel of candidate single nucleotide polymorphisms (SNPs) to assess genetic risk. Eighty-one HGG patients (18 grade IV and 63 grade III, 50M/31F) were included in the study. The median age at the time of radiotherapy was 48 years old (range 18-69). The median follow-up after the completion of radiotherapy was 79 months. A total of 44 patients (44/81, 54.3%) developed RIL during follow-up. Twenty-nine of the 44 patients developed consistent symptoms such as subcortical dementia (n = 28), gait disturbances (n = 12), and urinary incontinence (n = 9). The cumulative incidence of RIL was 21% at 12 months, 42% at 36 months, and 48% at 60 months. Age > 60 years, smoking, and the germline SNP rs2120825 (PPARg locus) were associated with an increased risk of RIL. Our study identified potential risk factors for the development of RIL (age, smoking, and the germline SNP rs2120825) and established the rationale for testing PPARg agonists in the prevention and management of late-delayed radiation-induced neurotoxicity.

Epidemiological, clinical, and genetic characteristics of paediatric genetic white matter disorders in Northern Finland.

AIM: To examine the epidemiological, clinical, and genetic characteristics of paediatric patients with genetic white matter disorders (GWMDs) in Northern Finland. METHOD: A longitudinal population-based cohort study was conducted in the tertiary catchment area of Oulu University Hospital from 1990 to 2019. Patients were identified retrospectively by International Statistical Classification of Diseases and Related Health Problems codes in hospital records and prospectively by attending physicians. Inclusion criteria were children younger than 18 years with defined GWMDs or genetic disorders associated with white matter abnormalities (WMAs) on brain magnetic resonance imaging. RESULTS: Eighty patients (mean age [SD] at the end of the study 11y [8y 6mo], range 0-35y; 45 males, 35 females) were diagnosed with a defined GWMD. The cumulative childhood incidence was 30 per 100 000 live births. Regarding those patients with 49 distinct GWMDs, 20% had classic leukodystrophies and 80% had genetic leukoencephalopathies. The most common leukodystrophies were cerebral adrenoleukodystrophy, Krabbe disease, and Salla disease. Additionally, 29 patients (36%) had genetic aetiologies not previously associated with brain WMAs or they had recently characterised GWMDs, including SAMD9L- and NHLRC2-related neurological disorders. Aetiology was mitochondrial in 21% of patients. The most common clinical findings were motor developmental delay, intellectual disability, hypotonia, and spasticity. INTERPRETATION: The cumulative childhood incidence of childhood-onset GWMDs was higher than previously described. Comprehensive epidemiological and natural history data are needed before future clinical trials are undertaken. What this paper adds Forty-nine distinct genetic white matter disorders (GWMDs) were identified, with 20% of cases being classic leukodystrophies. The cumulative childhood incidence of GWMDs was higher than described previously. A considerable proportion (36%) of GWMDs were previously undefined or recently characterised GWMDs. Mitochondrial aetiology was more common (21%) than previously reported.

Prevalence and risk factors for brain white matter changes in young and middle-aged participants with Brain Dock (brain screening): a registry database study and literature review.

This study aimed to determine the prevalence and risk factors for brain white matter changes in normal young and middle-aged participants who underwent Brain Dock (brain screening). We analyzed 5,000 consecutive healthy participants from the Brain Dock registry between August to December 2018. Age, sex, body mass index (BMI), medical history, deep subcortical white matter high intensity (DSWMH), periventricular high intensity (PVH), and enlargement of perivascular space (EPVS) were investigated in relation to age. The prevalence of DSWMH, PVH, and EPVS were 35.3%, 14.0%, and 17.8%, respectively. Multivariate logistic regression analyses for brain white matter changes were conducted. The significant risk factors in participants aged < 50 years were: age (OR:1.09, 95% CI:1.07-1.12), the female sex (1.29, 1.03-1.60), BMI obesity (1.86, 1.12-3.08), and hypertension (1.67, 1.18-2.35) for DSWMH; age (1.08, 1.04-1.13) and the female sex (1.56, 1.03-2.36) for PVH; and age (1.07, 1.05-1.10) and the female sex (0.77, 0.60-1.00) for EPVS. In conclusion, age was consistently identified as a significant risk factor in young and middle-aged participants. Some risk factors for brain white matter changes were identified even in young and middle-aged participants in this study. Further longitudinal studies should be done in the future.

Intracerebral Hemorrhage in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy: Prevalence, Clinical and Neuroimaging Features and Risk Factors.

BACKGROUND AND PURPOSE: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a monogenic cerebral small vessel disease. The role of intracerebral hemorrhage (ICH) in CADASIL remains elusive. The present study aims to investigate the prevalence, characteristics, and risk factors for ICH in CADASIL. METHODS: This retrospective cross-sectional study investigated ICH and cerebral microbleeds (CMBs) in brain susceptibility-weighted imaging or T2*-weighted gradient-recalled echo images of 127 Taiwanese patients with genetically confirmed CADASIL. We analyzed CMBs, lacunes, white matter hyperintensity, and perivascular space. The total small vessel disease score (range, 0-4) was calculated to estimate the overall magnetic resonance imaging burden of small vessel disease. Multivariate regression analysis was performed to identify factors related to ICH lesions in CADASIL. RESULTS: Thirty-seven ICH lesions, including 15 symptomatic and 22 asymptomatic lesions, were found in 27 (21.3% [95% CI, 14.0%-30.9%]) of the 127 patients with CADASIL. The thalamus and lobar regions were the most common ICH locations, and 72.7% of the lobar hemorrhages occurred silently. Patients with CADASIL with ICH lesions more often had hypertension and a higher total small vessel disease score than those without ICH (odds ratio [95% CI]: 3.22 [1.25-8.30] and 3.79 [1.51-9.51]). The presence of CMBs in the brain stem and a total CMB count >10 were independently associated with ICH lesions in patients with CADASIL, with odds ratio (95% CI) of 5.82 (1.80-18.80) and 3.83 (1.08-13.67), respectively. CONCLUSIONS: ICH is an underestimated but important manifestation of CADASIL. The location and number of CMBs are associated with the presence of ICH lesions in patients with CADASIL.

Genetic testing of leukodystrophies unraveling extensive heterogeneity in a large cohort and report of five common diseases and 38 novel variants.

This study evaluates the genetic spectrum of leukodystrophies and leukoencephalopathies in Iran. 152 children, aged from 1 day to 15 years, were genetically tested for leukodystrophies and leukoencephalopathies based on clinical and neuroradiological findings from 2016 to 2019. Patients with a suggestive specific leukodystrophy, e. g. metachromatic leukodystrophy, Canavan disease, Tay-Sachs disease were tested for mutations in single genes (108; 71%) while patients with less suggestive findings were evaluated by NGS. 108 of 152(71%) had MRI patterns and clinical findings suggestive of a known leukodystrophy. In total, 114(75%) affected individuals had (likely) pathogenic variants which included 38 novel variants. 35 different types of leukodystrophies and genetic leukoencephalopathies were identified. The more common identified disorders included metachromatic leukodystrophy (19 of 152; 13%), Canavan disease (12; 8%), Tay-Sachs disease (11; 7%), megalencephalic leukodystrophy with subcortical cysts (7; 5%), X-linked adrenoleukodystrophy (8; 5%), Pelizaeus-Merzbacher-like disease type 1 (8; 5%), Sandhoff disease (6; 4%), Krabbe disease (5; 3%), and vanishing white matter disease (4; 3%). Whole exome sequencing (WES) revealed 90% leukodystrophies and genetic leukoencephalopathies. The total diagnosis rate was 75%. This unique study presents a national genetic data of leukodystrophies; it may provide clues to the genetic pool of neighboring countries. Patients with clinical and neuroradiological evidence of a genetic leukoencephalopathy should undergo a genetic analysis to reach a definitive diagnosis. This will allow a diagnosis at earlier stages of the disease, reduce the burden of uncertainty and costs, and will provide the basis for genetic counseling and family planning.

Characterization of Leukoencephalopathy and Association With Later Neurocognitive Performance in Pediatric Acute Lymphoblastic Leukemia.

OBJECTIVES: The most common form of pediatric cancer is acute lymphoblastic leukemia (ALL). Magnetic resonance (MR) neuroimaging studies have revealed leukoencephalopathy (LE) in pediatric ALL, but the impact of LE on long-term neurocognitive performance remains unknown. This study aims to objectively characterize the prevalence, extent, and intensity of LE, and their association with later neurocognitive performance. MATERIALS AND METHODS: Pediatric patients (N = 377) treated for ALL without irradiation underwent MR neuroimaging at 4 time points throughout therapy (end of remission induction [MR1], end of consolidation [MR2], and week 31 [MR3] and week 120 [end therapy, MR4] of continuation treatment) and neurocognitive evaluations at the end of therapy and 2 years later. Generalized estimation equation models with logit link were developed to explore the association between LE prevalence and extent with time points throughout therapy, age at diagnosis (≤5 years or >5 years), treatment risk arm (low risk or standard/high risk), and sex. General linear models were also developed to investigate the association between neuroimaging metrics during treatment and neurocognitive performance at 2-year follow-up. RESULTS: The prevalence of LE was greatest (22.8%, 74/324) after consolidation therapy. The prevalence of LE increased at MR2 relative to MR1 regardless of treatment risk arm (both P's < 0.001), age group (both P's < 0.001), or sex (male, P < 0.001; female, P = 0.013). The extent of white matter affected also increased at MR2 relative to MR1 regardless of treatment risk arm (standard/high risk, P < 0.001; low risk, P = 0.004), age group (both P's < 0.001), or sex (male, P < 0.001; female, P = 0.001). Quantitative relaxation rates were significantly longer in LE compared with that in normal-appearing white matter in the same examination (T1, P < 0.001; T2, P < 0.001). The LE prevalence early in therapy was associated with increased parent ratings of conduct problems (P = 0.039) and learning difficulties (P = 0.036) at 2-year follow-up compared with that at the end of therapy. A greater extent of LE early in therapy was associated with decreasing performance on a measure of processing speed (P = 0.003) from the end of therapy to 2-year follow-up. A larger extent of LE at the end of therapy was associated with decreased performance in reading (P = 0.004), spelling (P = 0.003), and mathematics (P = 0.019) at 2-year follow-up and increasing problems with attention (omissions, P = 0.045; ß, P = 0.015) and memory (list A total recall, P = 0.010) at 2-year follow-up compared with that at the end of therapy. CONCLUSIONS: In this large cohort of pediatric patients treated for ALL without irradiation, asymptomatic LE during therapy can be seen in almost a quarter of patients, involves as much as 10% of the white matter volume, and is associated with decreasing neurocognitive performance, increasing parent reports of conduct problems, and learning difficulties in survivors.

Association Between Small Vessel Disease Markers, Medial Temporal Lobe Atrophy and Cognitive Impairment After Stroke: A Systematic Review and Meta-Analysis.

OBJECTIVES: Two-thirds of stroke survivors suffer from cognitive impairment, and up to one-third of them progress to dementia. However, the underlying pathogenesis is complex and controversial. Recent evidence has found that cerebral small vessel disease (SVD) markers and the Alzheimer's disease (AD) neuroimaging marker medial temporal lobe atrophy (MTLA), alone or in combination, contribute to the pathogenesis of poststroke cognitive impairment (PSCI). In the present systematic review and meta-analysis, we synthesized proof for these neuroimaging risk factors among stroke patients. MATERIALS AND METHODS: PUBMED, MEDLINE, EMBASE and the Cochrane Library were searched for studies investigating imaging predictors of cognitive impairment or dementia following stroke. Meta-analysis was conducted to compute the odds ratios (ORs). RESULTS: Thirteen studies were enrolled in the present study, and only ten of them, comprising 2713 stroke patients, were eligible for inclusion in the meta-analysis. MTLA was significantly correlated with PSCI (OR = 1.97, 95% CI: 1.48-2.62, I2 = 0.0%). In addition, white matter hyperintensities (WMH), as a neuroimaging marker of SVD, were associated with PSCI (OR = 1.17, 95% CI: 1.12-1.22, I2 = 0.0%). However, the presence of lacunar infarcts and enlarged perivascular spaces (EPVS) were not associated with the risk of PSCI. CONCLUSIONS: The findings of the present study suggest that MTLA and WMH were associated with an increased risk of PSCI.

Susceptibility Vessel Sign in Deep Perforating Arteries in Patients with Recent Small Subcortical Infarcts.

OBJECTIVES: Recent small subcortical infarcts (RSSI) are considered an acute manifestation of cerebral small vessel disease. Paramagnetic signals in perforating arteries supplying RSSI may be detected on T2*-relaxation derived sequences on MRI and is defined as susceptibility vessel sign (SVS). We aimed to study the prevalence of SVS in patients with RSSI, and explore whether its identification is related to cerebral small vessel disease markers. MATERIALS AND METHODS: We selected patients with RSSI identified on MRI during admission from a single-center stroke registry. The main demographic and clinical features, including vascular risk factors, were collected. Radiological features of RSSI and cerebral small vessel disease [white matter hyperintensities in deep and periventricular regions, enlarged perivascular spaces, lacunae, microbleeds, and brain atrophy] were described using validated qualitative scores. The presence of SVS was assessed on T2*gradient-echo or other susceptibility-weighted imaging. We compared the clinical and radiological features of patients with or without SVS in uni- and multivariate models. RESULTS: Out of 210 patients with an RSSI on an MRI, 35 (17%) showed SVS. The proportion of SVS+ patients was similar in different susceptibility imaging modalities (p=.64). Risk factor profiles and clinical course were similar in SVS+ and SVS- patients. SVS+ patients had a higher grade of deep white matter hyperintensities and brain atrophy, more lacunae (p=.001, p=.034, p=.022, respectively), and a similar degree of the rest of radiological variables, compared to SVS- patients. In the multivariate analysis, the grade of deep white matter hyperintensities was the only independent factor associated with SVS [OR 3.1 (95% CI, 1.5-6.4)]. CONCLUSIONS: SVS in patients with RSSI is uncommon and related to a higher grade of deep white matter hyperintensities. Pathophysiological mechanisms underlying the deposition of hemosiderin in the path of occluded perforating arteries are uncertain and might include endothelial dysfunction or embolic mechanisms.

Association of White Matter Hyperintensities and Cardiovascular Disease: The Importance of Microcirculatory Disease.

Cardiac and cerebrovascular diseases are currently the leading causes of mortality and disability worldwide. Both the heart and brain display similar vascular anatomy, with large conduit arteries running on the surface of the organ providing tissue perfusion through an intricate network of penetrating small vessels. Both organs rely on fine tuning of local blood flow to match metabolic demand. Blood flow regulation requires adequate functioning of the microcirculation in both organs, with loss of microvascular function, termed small vessel disease (SVD) underlying different potential clinical manifestations. SVD in the heart, known as coronary microvascular dysfunction, can cause chronic or acute myocardial ischemia and may lead to development of heart failure. In the brain, cerebral SVD can cause an acute stroke syndrome known as lacunar stroke or more subtle pathological alterations of the brain parenchyma, which may eventually lead to neurological deficits or cognitive decline in the long term. Coronary microcirculation cannot be visualized in vivo in humans, and functional information can be deduced by measuring the coronary flow reserve. The diagnosis of cerebral SVD is largely based on brain magnetic resonance imaging, with white matter hyperintensities, microbleeds, and brain atrophy reflecting key structural changes. There is evidence that such structural changes reflect underlying cerebral SVD. Here, we review interactions between SVD and cardiovascular risk factors, and we discuss the evidence linking cerebral SVD with large vessel atheroma, atrial fibrillation, heart failure, and heart valve disease.

Cerebral Microbleeds and Leukoencephalopathy in Critically Ill Patients With COVID-19.

BACKGROUND AND PURPOSE: We conducted this study to investigate the prevalence and distribution of cerebral microbleeds and leukoencephalopathy in hospitalized patients with coronavirus disease 2019 (COVID-19) and correlate with clinical, laboratory, and functional outcomes. METHODS: We performed a retrospective chart review of 4131 COVID-19 positive adult patients who were admitted to 3 tertiary care hospitals of an academic medical center at the epicenter of the COVID-19 pandemic in New York City from March 1, 2020, to May 10, 2020, to identify patients who had magnetic resonance imaging (MRI) of the brain. We evaluated the MRIs in detail, and identified a subset of patients with leukoencephalopathy and/or cerebral microbleeds. We compared clinical, laboratory, and functional outcomes for these patients to patients who had a brain MRI that did not show these findings. RESULTS: Of 115 patients who had an MRI of the brain performed, 35 (30.4%) patients had leukoencephalopathy and/or cerebral microbleeds. Patients with leukoencephalopathy and/or cerebral microbleeds had neuroimaging performed later during the hospitalization course (27 versus 10.6 days; P<0.001), were clinically sicker at the time of brain MRI (median GCS 6 versus 14; P<0.001), and had higher peak D-dimer levels (8018±6677 versus 3183±3482; P<0.001), lower nadir platelet count (116.9±62.2 versus 158.3±76.2; P=0.03), higher peak international normalized ratio (2.2 versus 1.57; P<0.001) values when compared with patients who had a brain MRI that did not show these findings. They required longer ventilator support (34.6 versus 9.1 days; P<0.001) and were more likely to have moderate and severe acute respiratory distress syndrome score (88.6% versus 23.8%, P<0.001). These patients had longer hospitalizations (42.1 versus 20.9 days; P<0.001), overall worse functional status on discharge (mRS 5 versus 4; P=0.001), and higher mortality (20% versus 9%; P=0.144). CONCLUSIONS: The presence of leukoencephalopathy and/or cerebral microbleeds is associated with a critical illness, increased mortality, and worse functional outcome in patients with COVID-19.